Viktor Grünwald, MD: It’s, of course, a combination. I think chemotherapy is not completely out. I think it’s reasonable to combine things because it takes some time to acquire an immune response. We’re not completely clear about this because we don’t have continuous monitoring of tumor response in these patients. But it seems to be a certain delay until you have some response. So, the question would be, if you kick in some chemotherapy, would it rescue patients, give them more time to get an immune response, where the release of antigens is something that is being discussed? These are all hypotheses. But if you ask me, “Is there a role for chemotherapy plus immunotherapy?”, I would say, “Yes, there is, and it’s worthwhile to explore.”

Ezra Cohen, MD: And, certainly, there are studies exploring it. So, we have data on single-agent pembrolizumab showing efficacy and good tolerability. We have data with nivolumab versus chemotherapy showing an improvement in overall survival. We have some biomarker data suggesting that PD-L1 may be an enrichment strategy for patients for PD-1 blockade. But we don’t select our patients based on PD-L1 expression. But, of course, the field isn’t stopping there. Kevin, there’s a lot more on the horizon with respect to immunotherapy. Tell us what’s going on, tell us what you’re excited about and where the field’s going to go.

Kevin Harrington, MD, PhD: I think it’s very difficult to predict exactly where the field is going to go, and that’s what makes it so exciting. What I do know is that there is significant clinical trial activity around other PD-targeted agents; in particular, around the PD-L1 axis. So, for instance, drugs such as durvalumab: the data set from the cohort of head and neck cancer patients, the 62 patients treated in the 1108 study with single-agent durvalumab, show that that is also an active agent with a response rate of around about 11%. We know that another PD-L1–targeted drug, avelumab, has activity again in an enlarged cohort in patients with head and neck cancers. We know that for at least 2 of these agents—nivolumab and durvalumab—there is a strategy to combine them with CTLA-4 blockade, respectively, with tremelimumab for durvalumab and ipilimumab for nivolumab.

Ezra Cohen, MD: Kevin, on that point, I’ll interrupt you for a second. But, please, if you don’t mind, what’s the rationale behind that? If you could just explain that.

Kevin Harrington, MD, PhD: In terms of the aspects of trying to drive an antitumor immune response, we’ve paid a great deal of attention to the checkpoint around the PD-1/PD-L1 access. But, of course, that is at the level of the effective phase of the immune response. Whereas if we go back a step and we really think about the priming phase, and the activation and licensing of those T cells for antitumor activity, the role of CTLA-4 blockade really gives us another level of activity, a second break that we can disengage and that we can allow for the immune system to become further activated.

So, this dual blockade has been demonstrated to be significantly active in other disease types, melanoma being the case-in-point whereby the double action of nivolumab and ipilimumab delivered response rates in the mid-50%. There was significant toxicity, but nonetheless, there were significant response rates. And we’re waiting for those final analyses to show the overall survival benefit. So, I think there is, again, an interest in doing those sorts of things in head and neck cancer.

Ezra Cohen, MD: Even though they’re both called checkpoint inhibitors, I wanted to clarify, for the audience, that they clearly hit different checkpoints in different parts of the immunotherapy cycle.

Kevin Harrington, MD, PhD: Yes, indeed, and potentially also in different compartments of the immune response. We also know it’s more complicated than maybe we’ve just described because we know that one of the roles of ipilimumab is it can deplete regulatory T cells within peripheral lymphoid tissues, but also actually within the tumor cell, the tumor mass itself. And so, there may be other multiplicities of activity.

I think the interaction of PD-1, PD-L1 inhibitors with CTLA-4 inhibitors is a really exciting area. Of course, we have randomized first-line phase III trials already underway, like in the case of the AstraZeneca KESTREL study. And it’s been planned, and indeed just activated, here in the United States with the CheckMate-651 study. In addition, there is a whole wave of new drugs coming down the various pharmaceutical pipelines. And I think that’s a cause for huge optimism and for huge enthusiasm because we have drugs that will engage with multiple aspects of the immune response, including the stimulatory side of the immune synapse—drugs such as CD137 and targeted drugs such as 4-1BB, OX40, CD40. I think those represent very exciting drugs.

And there’s also the opportunity, in fact, to engage other elements of the innate immune response; so, drugs that activate NK cells, drugs targeting KIR (killer cell immunoglobulin-like receptor) for instance, drugs that act as true innate activators, such as the toll-like receptor agonists—STING (stimulator of interferon gene) receptor agonists. And an area of particular interest to me, which, again, I have to declare a conflict, is the use of oncolytic virus therapies. Indeed, the drug talimogene laherparepvec (T-VEC), or IMLYGIC, which has been approved in the treatment of melanoma, is now being brought to bear in head and neck cancer with a phase Ib study that we hope will roll into a phase III study of T-VEC in combination with pembrolizumab. The idea there being that a tumor-specific virus infection acts as an immune stimulant, and an inflammatory stimulant will actually enable pembrolizumab to have a greater activity, systemically. I think that’s hugely exciting.

Ezra Cohen, MD: And, certainly, if the melanoma data are any indication, there’s reason to be excited with talimogene laherparepvec in combination with a checkpoint inhibitor. Kevin, I share your excitement. Tanguy, tell us a little bit more about some other combinations and how you see them coming into play in head and neck cancer.

Tanguy Y. Seiwert, MD: By and large, I would say, as an overarching theme, that we’re just starting to scratch the surface of immunotherapy. It’s a new modality. It is noncross-resistant with anything that we’ve done before—chemotherapy, radiation. It is a new modality. And if you think about it, 70% of head and neck tumors have some level of PD-L1 expression, some level of inflammation. But we only see responses in 15% to 18% of patients. So, the pool of patients who might benefit from combinations is huge. I believe that in the next 5 to 10 years, we’ll see leaps and bounds of progress. I’m an optimist, and I think many are optimistic because it’s a new modality, it’s a new mechanism, and there are clear indications that we can do better. And, as was pointed out, we see in other diseases that some of those combinations look very promising.

I think in the first-line setting right now, we have 2 strategies that clearly look promising: one being the combination with chemotherapy. And we, again, see data in lung cancer that look striking, combining a PD-1 inhibitor with chemotherapy. But at the same time, there’s also the other strategy looking at the combination with a second checkpoint inhibitor. Again, striking activity in melanoma, some activity in lung cancer. I think those 2 strategies are promising. And I wonder if they may actually hit different things because PD-L1 positivity versus PD-L1 negativity might actually make a difference. So, I think progress will be profound and probably will lead to first-line approval of one of those combinations or probably both.

But I also think there’s a ton of other targets, and I think Kevin actually mentioned many of the promising targets. So, I’m a big fan of making tumors inflamed. In fact, if you look at the data, noninflamed tumors, in my mind, are the most challenging tumors to go after. That’s not just PD-L1–negative tumors, but truly getting the T cells into the tumor. And I think T-VEC is one strategy. It has a very different profile from, actually, the immune checkpoints. STING may be another one, and there is great preclinical data. STING actually just entered clinical trials. We’re treating our first patient with head and neck cancer right now. So, I think there’s a lot to come.

I think the NK cell strategies, we’ll likely see data at SITC of the first strategy there. And again, I’m very curious to see this. Ultimately, there are other targets that may actually help work on T-regulatory cells, another immune suppressive mechanism. So, CTLA-4 targeting may do this. But there’s also the study called IDO. There are multiple drugs that are IDO inhibitors, and they may actually provide a less toxic alternative. And, again, we have to wait for the clinical data. But I think there are a large number of combinations; in fact, too many to list. There’s so much activity. And, ultimately, this is really good for patients.

You know if you go back 10 years, or even 5 years, there was very little clinical trial activity for head and neck cancer. But now we’re seeing a wealth of trials, so much interest. And I think it’s really important for patients to seek out trials, to go to centers that offer trials, because there’s a high chance, in my mind—and maybe I’m a little bit biased—that some of these combinations will hit and actually provide additional benefit. So, I’m an optimist. I think the future is bright, and immunotherapy will be important for many, many patients.

Ezra Cohen, MD: Yes, Tanguy, I share your biases. But, quite honestly, and not in a facetious way, I really do believe that the best therapy that we can offer to patients now is in the context of a clinical trial, because there is so much going on and so many treatments, especially new immunotherapies. And, again, to illustrate your point about the IDO inhibitors, if the data that we’re seeing in melanoma and non–small cell lung cancer translate into head and neck cancer, we’ve got a combination that has great potential. And, obviously, we’d like to see the data in head and neck cancer.

Transcript Edited for Clarity

Transcript:

Ezra Cohen, MD: What’s on the horizon, if I can put you on the spot?

Viktor Grünwald, MD: It’s, of course, a combination. I think chemotherapy is not completely out. I think it’s reasonable to combine things because it takes some time to acquire an immune response. We’re not completely clear about this because we don’t have continuous monitoring of tumor response in these patients. But it seems to be a certain delay until you have some response. So, the question would be, if you kick in some chemotherapy, would it rescue patients, give them more time to get an immune response, where the release of antigens is something that is being discussed? These are all hypotheses. But if you ask me, “Is there a role for chemotherapy plus immunotherapy?”, I would say, “Yes, there is, and it’s worthwhile to explore.”

Ezra Cohen, MD: And, certainly, there are studies exploring it. So, we have data on single-agent pembrolizumab showing efficacy and good tolerability. We have data with nivolumab versus chemotherapy showing an improvement in overall survival. We have some biomarker data suggesting that PD-L1 may be an enrichment strategy for patients for PD-1 blockade. But we don’t select our patients based on PD-L1 expression. But, of course, the field isn’t stopping there. Kevin, there’s a lot more on the horizon with respect to immunotherapy. Tell us what’s going on, tell us what you’re excited about and where the field’s going to go.

Kevin Harrington, MD, PhD: I think it’s very difficult to predict exactly where the field is going to go, and that’s what makes it so exciting. What I do know is that there is significant clinical trial activity around other PD-targeted agents; in particular, around the PD-L1 axis. So, for instance, drugs such as durvalumab: the data set from the cohort of head and neck cancer patients, the 62 patients treated in the 1108 study with single-agent durvalumab, show that that is also an active agent with a response rate of around about 11%. We know that another PD-L1–targeted drug, avelumab, has activity again in an enlarged cohort in patients with head and neck cancers. We know that for at least 2 of these agents—nivolumab and durvalumab—there is a strategy to combine them with CTLA-4 blockade, respectively, with tremelimumab for durvalumab and ipilimumab for nivolumab.

Ezra Cohen, MD: Kevin, on that point, I’ll interrupt you for a second. But, please, if you don’t mind, what’s the rationale behind that? If you could just explain that.

Kevin Harrington, MD, PhD: In terms of the aspects of trying to drive an antitumor immune response, we’ve paid a great deal of attention to the checkpoint around the PD-1/PD-L1 access. But, of course, that is at the level of the effective phase of the immune response. Whereas if we go back a step and we really think about the priming phase, and the activation and licensing of those T cells for antitumor activity, the role of CTLA-4 blockade really gives us another level of activity, a second break that we can disengage and that we can allow for the immune system to become further activated.

So, this dual blockade has been demonstrated to be significantly active in other disease types, melanoma being the case-in-point whereby the double action of nivolumab and ipilimumab delivered response rates in the mid-50%. There was significant toxicity, but nonetheless, there were significant response rates. And we’re waiting for those final analyses to show the overall survival benefit. So, I think there is, again, an interest in doing those sorts of things in head and neck cancer.

Ezra Cohen, MD: Even though they’re both called checkpoint inhibitors, I wanted to clarify, for the audience, that they clearly hit different checkpoints in different parts of the immunotherapy cycle.

Kevin Harrington, MD, PhD: Yes, indeed, and potentially also in different compartments of the immune response. We also know it’s more complicated than maybe we’ve just described because we know that one of the roles of ipilimumab is it can deplete regulatory T cells within peripheral lymphoid tissues, but also actually within the tumor cell, the tumor mass itself. And so, there may be other multiplicities of activity.

I think the interaction of PD-1, PD-L1 inhibitors with CTLA-4 inhibitors is a really exciting area. Of course, we have randomized first-line phase III trials already underway, like in the case of the AstraZeneca KESTREL study. And it’s been planned, and indeed just activated, here in the United States with the CheckMate-651 study. In addition, there is a whole wave of new drugs coming down the various pharmaceutical pipelines. And I think that’s a cause for huge optimism and for huge enthusiasm because we have drugs that will engage with multiple aspects of the immune response, including the stimulatory side of the immune synapse—drugs such as CD137 and targeted drugs such as 4-1BB, OX40, CD40. I think those represent very exciting drugs.

And there’s also the opportunity, in fact, to engage other elements of the innate immune response; so, drugs that activate NK cells, drugs targeting KIR (killer cell immunoglobulin-like receptor) for instance, drugs that act as true innate activators, such as the toll-like receptor agonists—STING (stimulator of interferon gene) receptor agonists. And an area of particular interest to me, which, again, I have to declare a conflict, is the use of oncolytic virus therapies. Indeed, the drug talimogene laherparepvec (T-VEC), or IMLYGIC, which has been approved in the treatment of melanoma, is now being brought to bear in head and neck cancer with a phase Ib study that we hope will roll into a phase III study of T-VEC in combination with pembrolizumab. The idea there being that a tumor-specific virus infection acts as an immune stimulant, and an inflammatory stimulant will actually enable pembrolizumab to have a greater activity, systemically. I think that’s hugely exciting.

Ezra Cohen, MD: And, certainly, if the melanoma data are any indication, there’s reason to be excited with talimogene laherparepvec in combination with a checkpoint inhibitor. Kevin, I share your excitement. Tanguy, tell us a little bit more about some other combinations and how you see them coming into play in head and neck cancer.

Tanguy Y. Seiwert, MD: By and large, I would say, as an overarching theme, that we’re just starting to scratch the surface of immunotherapy. It’s a new modality. It is noncross-resistant with anything that we’ve done before—chemotherapy, radiation. It is a new modality. And if you think about it, 70% of head and neck tumors have some level of PD-L1 expression, some level of inflammation. But we only see responses in 15% to 18% of patients. So, the pool of patients who might benefit from combinations is huge. I believe that in the next 5 to 10 years, we’ll see leaps and bounds of progress. I’m an optimist, and I think many are optimistic because it’s a new modality, it’s a new mechanism, and there are clear indications that we can do better. And, as was pointed out, we see in other diseases that some of those combinations look very promising.

I think in the first-line setting right now, we have 2 strategies that clearly look promising: one being the combination with chemotherapy. And we, again, see data in lung cancer that look striking, combining a PD-1 inhibitor with chemotherapy. But at the same time, there’s also the other strategy looking at the combination with a second checkpoint inhibitor. Again, striking activity in melanoma, some activity in lung cancer. I think those 2 strategies are promising. And I wonder if they may actually hit different things because PD-L1 positivity versus PD-L1 negativity might actually make a difference. So, I think progress will be profound and probably will lead to first-line approval of one of those combinations or probably both.

But I also think there’s a ton of other targets, and I think Kevin actually mentioned many of the promising targets. So, I’m a big fan of making tumors inflamed. In fact, if you look at the data, noninflamed tumors, in my mind, are the most challenging tumors to go after. That’s not just PD-L1–negative tumors, but truly getting the T cells into the tumor. And I think T-VEC is one strategy. It has a very different profile from, actually, the immune checkpoints. STING may be another one, and there is great preclinical data. STING actually just entered clinical trials. We’re treating our first patient with head and neck cancer right now. So, I think there’s a lot to come.

I think the NK cell strategies, we’ll likely see data at SITC of the first strategy there. And again, I’m very curious to see this. Ultimately, there are other targets that may actually help work on T-regulatory cells, another immune suppressive mechanism. So, CTLA-4 targeting may do this. But there’s also the study called IDO. There are multiple drugs that are IDO inhibitors, and they may actually provide a less toxic alternative. And, again, we have to wait for the clinical data. But I think there are a large number of combinations; in fact, too many to list. There’s so much activity. And, ultimately, this is really good for patients.

You know if you go back 10 years, or even 5 years, there was very little clinical trial activity for head and neck cancer. But now we’re seeing a wealth of trials, so much interest. And I think it’s really important for patients to seek out trials, to go to centers that offer trials, because there’s a high chance, in my mind—and maybe I’m a little bit biased—that some of these combinations will hit and actually provide additional benefit. So, I’m an optimist. I think the future is bright, and immunotherapy will be important for many, many patients.

Ezra Cohen, MD: Yes, Tanguy, I share your biases. But, quite honestly, and not in a facetious way, I really do believe that the best therapy that we can offer to patients now is in the context of a clinical trial, because there is so much going on and so many treatments, especially new immunotherapies. And, again, to illustrate your point about the IDO inhibitors, if the data that we’re seeing in melanoma and non–small cell lung cancer translate into head and neck cancer, we’ve got a combination that has great potential. And, obviously, we’d like to see the data in head and neck cancer.